This is a revised application in response to RFA: DK-02-028 for the establishment of the George M. O'Brien Kidney Research Center at the University of Texas Health Science Center. The application focuses on the response of the kidney to diverse forms of injury with the goal of identifying genetic factors and mechanisms of development of diabetic and polycystic kidney disease. The Center is composed of three scientific projects, one core, and three feasibility/developmental projects that bring together scientists from the Departments of Medicine, Cell and Structural Biology, Physiology, and the Institute of Biotechnology at the University of Texas Health Science Center at San Antonio and the Department of Genetics at the Southwest Foundation for Biomedical Research. In Project 1, Dr. Abboud will investigate a positional candidate gene, tight junction protein-1 (TJP-1) to identify DNA sequence variants that are responsible for the linkage to albuminura. In Project 2, Dr. Kasinath will explore the signaling mechanisms by which hyperinsulinemia results in protein translation and matrix accumulation in the db/db mouse model of type II diabetes. In Project 3, Dr. Chen, will explore the role of nekl kinase in the pathogenesis of polycystic kidney disease. In Project 4 (Development/Feasibility) Dr. Pergola explores microcirculatory responses to manipulations of the renin-angiotensin system as a potential tool to identify patients at risks for development of diabetic nephropathy. In Project 5 (Development/Feasibility), Dr. Gooch will study the role of calcineurin in IGF1 and TGFbeta signaling as it pertains to diabetic nephropathy. Project 6 (Development/Feasibility), Dr. Rincon-Choles will characterize kidney phenotype and identify quantitative trait loci influencing diabetic nephropathy in a pedigreed and genotyped colony of baboons with type II diabetes. Four of the six projects will utilize the services of the Morphology Core, and three of the six projects will utilize the Transgenic Core Facility. It is anticipated that the studies will advance the understanding of genetic, biochemical, and cellular factors that modulate renal response to injury.